We propose to rationally design, synthesize and test a series of advanced bioadhesive microbicidal vehicles which are triggered to undergo changes in their rheological properties by contact with seminal proteases. In fact, the same proteases that cause the liquefaction of the semen will cause liquefaction of the gel microbicide. We believe this approach will drastically increase the bioavailability of active anti-HIV components when they are needed most, by increasing transport properties without compromising coating. These materials will be constructed of bioresponsive polymers that in themselves are active or are formulated to contain active agents. This project is amongst the first to apply contemporary polymer synthesis methods, knowledge of bioresponsive polymer systems, and recent understanding of formulations and drug delivery in the vagina, to the compelling problem of development of microbicides for HIV prevention. Our approach addresses the physiology of the vagina and coitus, and then engineers materials which respond to environmental changes throughout their deployment life cycle. This will result in what we believe will be highly efficacious next generation microbicidal delivery vehicles. The bioresponsive formulations will be engineered to enhance the normal physiology of the vagina, to efficiently spread and adhere to tissue, and to provide a protective microbicidal coating. Moreover, the formulations will be designed to undergo sol-to-gel-to-sol phase transitions in response to physiological changes during deployment: i) topically applied as a low viscosity fluid, ii) triggered to gel by mixing of two components, thus forming a retained protective coating, and iii) undergoing reduction in viscosity, but not surface coating, through polymer structural changes triggered by contact with semen.